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Bridging What is Known and What is Not Known FDA Perspective and Response

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Applies to pharmaceuticals: Demonstration of Safety and Effectiveness ' ... Derived from pregnant mare's urine '0.625 mg' is a convention: does not quantitate amounts ... – PowerPoint PPT presentation

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Title: Bridging What is Known and What is Not Known FDA Perspective and Response


1
Bridging What is Known and What is Not
KnownFDA Perspective and Response
  • Janet Woodcock, M.D.
  • Director, Center for Drug Evaluation and Research
  • Food and Drug Administration

2
Topics
  • Role of FDA Drug Regulation
  • Estrogen and progestin drugs approved for
    menopausal conditions
  • Impact of WHI Results
  • Question of generalizability of findings
  • Implications of WHI for Risk Management
  • Conclusions

3
FDA Drug Regulation
  • Applies to pharmaceuticals Demonstration of
    Safety and Effectiveness
  • Dietary Supplements regulated under a different
    law - no FDA review of clinical data

4
Requirements for Pharmaceuticals Effectiveness
  • Demonstrated in adequate and well controlled
    trials
  • Applies only to indications in label
  • For chronic administration demonstration of
    long-term effectiveness not required
  • Advertising limited to approved indications and
    must conform to the data

5
Requirements for Pharmaceuticals Safety
  • No drug is absolutely safe
  • Safety benefits exceed risks for defined
    population and use
  • Longer term risks difficult to assess
  • Challenges of randomized trials
  • Positive benefit-risk may not apply to
    off-label use

6
Estrogen and Progestin Drugs Approved for
Menopausal Conditions
  • Five approved combination products four oral,
    one transdermal patch
  • Fifteen estrogen products oral, transdermal
    patches, injections, topical gel, vaginal ring
  • Six progestins oral, injection and gel

7
Approved Indications for Menopausal Conditions
  • Vasomotor symptoms
  • Vulvar vaginal atrophy
  • Prevention of osteoporosis
  • Not approved for
  • Prevention of cardiovascular disease
  • Hormone replacement

8
Treatment of Vasomotor Symptoms Current
Standards
  • Trial design 3 month placebo-controlled,
    multiple dose, 60-100 subjects/group
  • Endpoints
  • Clinically statistically significant reduction
    in frequency and severity of hot flashes weeks
    4-12.

9
Treatment of Vulvar Vaginal Atrophy
  • Trial design 3 month placebo- controlled,
    multiple dose,
  • 60-100 subjects/group
  • Endpoints
  • Statistically significant at 12 weeks
  • Symptom reduction
  • Lowering of vaginal pH
  • Improvement in maturation index

10
Prevention of Osteoporosis
  • Trial design 2 yr placebo controlled,
    typically 150-300 subjects
  • Endpoints
  • Lumbar spine bone mineral density

11
Estrogens Progestins, and Estrogens, Approved
for Prevention of Postmenopausal Osteoporsis
  • Product Active Ingredients
  • Activella estradiol/norethindrone
  • Femhrt ethinyl estradiol/norethindrone
  • Ortho-Prefest estradiol/norgestimate
  • Estrace estradiol
  • Ogen estropipate
  • Ortho-est estropipate
  • Vivelle (patch) estradiol
  • Climara (patch) estradiol

12
FDA- approved Non-estrogens for Treatment and
Prevention of Premenopausal Osteoporosis
  • Drug Class
  • Alendronate Bisphosphonate
  • Risedronate Bisphosphonate
  • Raloxifene SERM

13
Pre-WHI Safety Labeling Prempro
  • Warnings section known risks discussed
  • Induction of malignant neoplasms, including
    reports of moderately increased risk of breast
    cancer
  • Thromboembolic disorders including venous TE
  • Precautions Section A relationship between
    estrogen.. therapy and reduction of
    cardiovascular disease has not been proven

14
Impact of WHI Results on Menopausal Drug
Development
  • FDA considering public Advisory Committee Meeting
  • Impact on current labels
  • Trial length for safety data
  • Trial size for population experience
  • Generalizability of WHI results

15
Generalizability of WHI Results What do results
with Prempro imply for other estrogen/progestin
drugs
  • Two issues
  • Composition
  • Dose

16
Composition
  • Prempro .625 mg conjugated equine estrogens
    (CEE)
  • 2.5 or 5.0 mg medroxyprogesterone acetate
  • CEE Complex mixture

17
Composition of Premarin Component of Prempro
  • Derived from pregnant mares urine
  • 0.625 mg is a convention does not quantitate
    amounts
  • Multiple estrogen components pharmacologic
    characteristics of separate components not well
    characterized

18
Sodium Estrogen Sulfate mg/.625 mg tablet
  • Estrone .370
  • Equilin .168
  • 17-?- Dihydroequilin .102
  • 17-?- Estradiol .027
  • 17-?- Dihydroequilin .011
  • 17-?- Dihydroequilenin .011
  • 17-?- Dihydroequilenin .015
  • 17-?- Estradiol .005

8,9-Dehydroestrone .026 Equilenin .015
19
Composition Estrogens
  • Premarin contains unique equine estrogens in
    addition to estrone/estradiol
  • Equine estrogens may have different
    pharmacodynamic properties
  • Only two other approved products contain equine
    estrogens

20
Composition Progestins
  • Premarin also contains progestins - activity not
    known
  • Medroxyprogesterone acetate not a component of
    any other combination product

21
Dosage
  • Original estrogenic potency assignment based on a
    rat bioassay
  • Effects on rat do not parallel human
  • Pharmacokinetic difference among estrogens

22
Pharmacokinetic Studies
  • Estrogen Estrone Equilin
    8,9-DHE
  • Measured dose
  • or AUC
  • mg per 1.25mg dose .740 .336 .052
  • ng. Hr/ml AUC
  • Total plasma 94.2 43.1 13.6
  • Ketone
  • Unconj. plasma 4.08 1.2 .07
  • Ketone
  • Total plasma 8.57 10.6 6.62
  • 17 ? diol
  • Unconj. Plasma 0.66 1.06 0.33
  • 17 ? diol

23
  • Synthetic Generic Conjugated Estrogens
  • Website
  • http//www.fda.gov/cder/cepage.htm

24
Generalizability Dose
  • Drug toxicities are frequently dose related
  • WHI toxicity findings are generally congruent
    with potential class effects of estrogen and
    progestin
  • Not possible to extrapolate dose/toxicity
    findings directly to other related products

25
Risk Management Implications of WHI findings
  • Prevention indications Need to be assured of
    positive benefit/risk analysis in people without
    symptoms
  • Minimizing risk Data questions
  • Relationship of dose or duration to toxicity
  • Relationship of route of administration to
    toxicity

26
Risk Management Implications of WHI findings
  • Maximizing benefit
  • Women with more severe menopausal symptoms
  • Women at higher risk of osteoporosis

27
Risk Management Information Dissemination
  • Informative product labels
  • Patient education efforts by companies
  • Responsible advertising promotion

28
Summary
  • WHI results provide important additional risk
    information on estrogen/progestin combinations
  • Quantitative extrapolation to similar products
    not possible
  • There are implications for new drug development
    in this area
  • It is imperative that accurate information be
    available to prescribers and patients
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